High immunoglobulin G2 (IgG2) and low IgG4 levels are associated with human resistance to Plasmodium falciparum malaria

Abstract

There is accumulating evidence for a role of immunoglobulin G (IgG) in protection against malarial infection and disease. Only IgG1 and IgG3 are considered cytophilic and protective against P. falciparum, whereas IgG2 and IgG4 were thought to be neither and even to block protective mechanisms. However, no clear pattern of association between isotypes and protection has so far emerged. We analyzed the isotypic distribution of the IgG response to conserved epitopes and P. falciparum blood-stage extract in 283 malaria-exposed individuals whose occurrence of infection and malaria attack had been monitored for about 1 year. Logistic regression analyses showed that, at the end of the season of transmission, high levels of IgG2 to RESA and to MSP2 epitopes were associated with low risk of infection. Indeed, IgG2 is able to bind FcgammaRIIA in individuals possessing the H131 allele, and we showed that 70% of the study subjects had this allele. Also, high specific IgG4 levels were associated with an enhanced risk of infection and with a high risk of malaria attack. Moreover, specific IgG2 and IgG3 levels, as well as the IgG2/IgG4 and IgG3/IgG4 ratios, increased with the age of subjects, in parallel with the protection against infection and disease. IgG4 likely competes with cytophilic antibodies for antigen recognition and may therefore block cytotoxicity mediated by antibody-activated effector cells. In conclusion, these results favor a protective role of IgG3 and IgG2, which may activate effector cells through FcgammaRIIA, and provide evidence for a blocking role of IgG4 in malarial infection and disease.

FIG. 1

Anti-P. falciparum extract IgG subclass levels versus age in sera from 248 subjects at period P2. Ab levels are expressed as arbitrary units; curves predicted by polynomial regression analysis are shown. (A to D) Anti-P. falciparum extract IgG2 (A), anti-P. falciparum extract IgG3 (B), IgG2/IgG4 (C), and IgG3/IgG4 (D) ratios by age. AU, arbitrary units.

FIG. 2

Isotype responses and risk of infection: odds ratio for IgG4 in the presence of interaction with IgG2 at P1 (solid bar) and P2 (dotted bar). The odds between the lowest IgG4 quintile (IgG4 = 1) and the highest IgG4 quintile (IgG4 = 5) are shown with 95% CI values for each IgG2 quintile. The odds were no longer significant when IgG2 levels were high (IgG2 = 4 and IgG2 = 5).